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Cooperative activation of cyclobutanones and olefins leads to bridged ring systems by a catalytic [4 + 2] coupling.

Ko HM, Dong G - Nat Chem (2014)

Bottom Line: Bridged ring systems are widely found in natural products, and successful syntheses of them frequently feature intramolecular Diels-Alder reactions.Here, we describe a complementary approach that provides access to these structures through the C-C activation of cyclobutanones and their coupling with olefins.Various alkenes have been coupled with cyclobutanones to provide a range of bridged skeletons.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, USA.

ABSTRACT
Bridged ring systems are widely found in natural products, and successful syntheses of them frequently feature intramolecular Diels-Alder reactions. These reactions are subclassified as either type I or type II depending on how the diene motif is tethered to the rest of the substrate (type I are tethered at the 1-position of the diene and type II at the 2-position). Although the type I reaction has been used with great success, the molecular scaffolds accessible by the type II reactions are limited by the strain inherent in the formation of an sp(2) carbon at a bridgehead position. Here, we describe a complementary approach that provides access to these structures through the C-C activation of cyclobutanones and their coupling with olefins. Various alkenes have been coupled with cyclobutanones to provide a range of bridged skeletons. The ketone group of the products serves as a convenient handle for downstream functionalization.

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Proposed catalytic cycleThe key features include using metal-ligand cooperative activation of cyclobutanones and in situ carbonyl group protection to avoid decarbonylation.
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Figure 2: Proposed catalytic cycleThe key features include using metal-ligand cooperative activation of cyclobutanones and in situ carbonyl group protection to avoid decarbonylation.

Mentions: Our strategy is inspired by a “cofactor”-assisted C–C activation mode initially developed by Jun,40–42 which utilizes 2-amino-3-methylpyridine as a co-catalyst to generate an imine intermediate that serves as a directing group for cleaving the imine α C–C bond. This strategy has been effectively utilized to cleave medium to large cyclic ketimines in the presence of alkenes to afford ring-opened products (Fig. 1c). However, to the best of our knowledge, utilization of this mode in small-ring activation has not been reported previously. We hypothesized that employment of 2-amino-3-methylpyridine as a co-catalyst would benefit the desired intramolecular cyclobutanone-olefin coupling, depicted in Fig. 2. The amine would first form an imine with the cyclobutanone, which would then direct C–C cleavage through forming a chelation complex with the metal (e.g. Rh). Subsequent olefin migratory insertion followed by reductive elimination is expected to provide the bridged scaffold and regenerate the metal catalyst. Finally, the resulting imine can be hydrolyzed to give the bridged-ketone product and 2-amino-3-methylpyridine, which can be recycled. Hence, this strategy, distinct from the previous cyclobutanone activations,31–32, 28 can ease the C–C cleavage but more importantly prevent the aforementioned decarbonylation problem, because the carbonyl group would be in situ protected by the imine formation. Moreover, in principle, both the transition metal and the aminopyridine can be catalytic.


Cooperative activation of cyclobutanones and olefins leads to bridged ring systems by a catalytic [4 + 2] coupling.

Ko HM, Dong G - Nat Chem (2014)

Proposed catalytic cycleThe key features include using metal-ligand cooperative activation of cyclobutanones and in situ carbonyl group protection to avoid decarbonylation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150356&req=5

Figure 2: Proposed catalytic cycleThe key features include using metal-ligand cooperative activation of cyclobutanones and in situ carbonyl group protection to avoid decarbonylation.
Mentions: Our strategy is inspired by a “cofactor”-assisted C–C activation mode initially developed by Jun,40–42 which utilizes 2-amino-3-methylpyridine as a co-catalyst to generate an imine intermediate that serves as a directing group for cleaving the imine α C–C bond. This strategy has been effectively utilized to cleave medium to large cyclic ketimines in the presence of alkenes to afford ring-opened products (Fig. 1c). However, to the best of our knowledge, utilization of this mode in small-ring activation has not been reported previously. We hypothesized that employment of 2-amino-3-methylpyridine as a co-catalyst would benefit the desired intramolecular cyclobutanone-olefin coupling, depicted in Fig. 2. The amine would first form an imine with the cyclobutanone, which would then direct C–C cleavage through forming a chelation complex with the metal (e.g. Rh). Subsequent olefin migratory insertion followed by reductive elimination is expected to provide the bridged scaffold and regenerate the metal catalyst. Finally, the resulting imine can be hydrolyzed to give the bridged-ketone product and 2-amino-3-methylpyridine, which can be recycled. Hence, this strategy, distinct from the previous cyclobutanone activations,31–32, 28 can ease the C–C cleavage but more importantly prevent the aforementioned decarbonylation problem, because the carbonyl group would be in situ protected by the imine formation. Moreover, in principle, both the transition metal and the aminopyridine can be catalytic.

Bottom Line: Bridged ring systems are widely found in natural products, and successful syntheses of them frequently feature intramolecular Diels-Alder reactions.Here, we describe a complementary approach that provides access to these structures through the C-C activation of cyclobutanones and their coupling with olefins.Various alkenes have been coupled with cyclobutanones to provide a range of bridged skeletons.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, USA.

ABSTRACT
Bridged ring systems are widely found in natural products, and successful syntheses of them frequently feature intramolecular Diels-Alder reactions. These reactions are subclassified as either type I or type II depending on how the diene motif is tethered to the rest of the substrate (type I are tethered at the 1-position of the diene and type II at the 2-position). Although the type I reaction has been used with great success, the molecular scaffolds accessible by the type II reactions are limited by the strain inherent in the formation of an sp(2) carbon at a bridgehead position. Here, we describe a complementary approach that provides access to these structures through the C-C activation of cyclobutanones and their coupling with olefins. Various alkenes have been coupled with cyclobutanones to provide a range of bridged skeletons. The ketone group of the products serves as a convenient handle for downstream functionalization.

Show MeSH
Related in: MedlinePlus